Biomedical subjects

R A Soslow

Publications and source records attributed to R A Soslow.

At least 19 recordsLinked to original sources

PubMed2007

Tumor promoting properties of the ETS protein MEF in ovarian cancer.

We have previously shown that MEF (myeloid ELF1-like factor, also known as ELF4) functions as a transcriptional activator of the interleukin (IL)-8, perforin, granulocyte macrophage-colony stimulating factor (GM-CSF) and IL-3 genes in hematopoietic cells. MEF is also expressed in non-hematopoietic tissues including certain ovarian cancer cells. To define the function of MEF in these cells, we examined primary human ovarian epithelial tumors and found that MEF is expressed in a significant proportion of ovarian carcinomas, and in the CAOV3 and SKOV3 ovarian cancer cell lines, but not in normal ovarian surface epithelium. Manipulating MEF levels in these cell lines altered their behavior; reducing MEF levels, using short hairpin RNA expressing vectors, significantly inhibited the proliferation of SKOV3 and CAOV3 cells in culture, and impaired the anchorage-independent growth of CAOV3 cells. Overexpression of MEF in SKOV3 cells (via retroviral transduction) significantly increased their growth rate, enhanced colony formation in soft agar and promoted tumor formation in nude mice. The oncogenic activity of MEF was further shown by the ability of MEF to transform NIH3T3 cells, and induce their tumor formation in nude mice. MEF is an important regulator of the tumorigenic properties of ovarian cancer cells and could be used a therapeutic target in ovarian cancer.

Animals↗

PubMed2006

Clinicopathologic features of early adenocarcinoma of the cervix initially managed with cervical conization.

OBJECTIVE: To evaluate the clinicopathologic features of microinvasive adenocarcinoma of the cervix in order to guide the management of patients with this disease. MATERIALS AND METHODS: A retrospective review was conducted of patients diagnosed with early invasive, 1 mm and 2 mm and 3 mm and 4 mm and <or=5 mm. Three patients were treated with a conization only, 4 patients were treated with a simple hysterectomy, 25 patients were treated with a radical hysterectomy (RH) and PLN dissection (PLND), and 1 patient was treated with a radical trachelectomy and PLND. Ten patients had positive conization margins for invasive cancer, 3 patients had margins positive for adenocarcinoma in situ, 14 patients had negative margins, and in 6 patients the margin status could not be evaluated. Of the 10 patients with positive margins, 5 of 10 (50%) had residual disease in the subsequent surgical specimen. Three patients who underwent definitive management with conization alone originally had positive margins, underwent a second repeat conization, and are included in this group. Of the 16 patients with negative margins, no patient had residual disease in a subsequent surgical specimen. Of the 25 patients who underwent a RH and PLND, none had parametrial involvement and none had PLN involvement. All patients remained without evidence of disease at median follow-up of 30 months. CONCLUSIONS: Historically, the standard management of early invasive adenocarcinoma of the cervix has been controversial, and some clinicians continue to favor radical treatments. Based on the absence of parametrial spread and PLN involvement in early lesions, physicians and patients should consider treatment with conization with negative margins (when future fertility is desired) or simple hysterectomy. Prospective studies are required to document the safety of this approach.

Adenocarcinoma↗

PubMed2006

High frequency of beta-catenin mutations in borderline endometrioid tumours of the ovary.

Some low-grade endometrioid carcinomas arise from a background of endometrioid tumours of borderline malignancy. To determine the molecular mechanisms involved in the initiation of endometrioid carcinoma, the present study investigated whether the genetic alterations reported in these tumours (mutations in PTEN, KRAS, and beta-catenin genes, and microsatellite instability) are already present in endometrioid tumours of borderline malignancy. Eight endometrioid tumours of borderline malignancy were studied. By immunohistochemistry, beta-catenin was expressed in the nuclei of all tumours, suggesting the presence of stabilizing beta-catenin mutations. By mutational analysis, five different beta-catenin mutations were found in seven of eight cases (90%), affecting codons 32, 33, and 37. In contrast, only one tumour harboured a PTEN mutation, which affected codon 130. Neither KRAS mutations nor microsatellite instability was detected. A review of the literature indicated that beta-catenin mutations are characteristic of well-differentiated endometrioid carcinomas, since they were present in nearly 60% of grade I but in less of 3% of grade III tumours. In conclusion, the present study identifies beta-catenin mutation as a nearly constant molecular alteration in borderline endometrioid tumours, whereas PTEN and KRAS mutations and microsatellite instability are very infrequent. The findings in the present study, and previously reported data, strongly suggest that beta-catenin mutation is an early event in endometrioid ovarian carcinogenesis, and that it is involved in the development of low-grade endometrioid tumours.

Adult↗

PubMed2002

Characterization of cyclooxygenase-2 (COX-2) during tumorigenesis in human epithelial cancers: evidence for potential clinical utility of COX-2 inhibitors in epithelial cancers.

Increased prostaglandins (PGs) are associated with many inflammatory pathophysiological conditions; and are synthesized from arachidonic acid by either of 2 enzymes, cyclooxygenase-1 (COX-1) or -2 (COX-2). Recent epidemiologic, expression, and pharmacologic studies suggest COX-2 derived metabolites also play a functional role in the maintenance of tumor viability, growth and metastasis. Archival and/or prospectively collected human tissues were prepared for immunohistochemistry, and representative cases assayed via Western blot, RT-PCR, or TAQman analysis. Consistent overexpression of COX-2 was observed in a broad range of premalignant, malignant, and metastatic human epithelial cancers. COX-2 was detected in ca. 85% of the hyperproliferating, dysplastic, and neoplastic epithelial cells, and in the existing and angiogenic vasculature within and adjacent to hyperplastic/neoplastic lesions. These data collectively imply COX-2 may play an important role during premalignant hyperproliferation, as well as the later stages of invasive carcinoma and metastasis in various human epithelial cancers.

Cyclooxygenase 2↗

PubMed2001

Hand-assisted demucosalized gastrocystoplasty comparing different tissue closure methods.

OBJECTIVES: To perform experiments to determine whether a new tissue sealant (SynthaSeal) could be an alternative for suture closure in minimally invasive bladder autoaugmentation gastrocystoplasty using demucosalized stomach. Alternative methods to suture closure for tissue approximation such as laser tissue welding and fibrin glue have been reported. METHODS: Minimally invasive autoaugmentation gastrocystoplasty with demucosalized stomach was performed on 14 female mongrel dogs. Two dogs were used to refine the technique. The remaining dogs were assigned to a suture group (n = 6) or a SynthaSeal group (n = 6). Anastomoses were performed using either SynthaSeal or suture. The in vivo bladder volumes and pressures of the groups were measured before and after gastrocystoplasty. The animals were studied on day 14. Samples of the anastomotic area were taken to measure the tensile strength and stress. Histologic analysis was conducted to assess tissue healing. The anastomotic time was recorded for each group. RESULTS: The tensile strength of the anastomoses in the SynthaSeal group was significantly increased (9.99 +/- 1.14 Newtons) compared with the suture group (5.66 +/- 0.97 Newtons) (P <0.05). The breaking stress comparisons and anastomosis times were equivalent between the two groups. The histologic evaluation revealed minor tissue devitalization and a normal inflammatory response in both groups. CONCLUSIONS: Minimally invasive gastrocystoplasty using demucosalized stomach can be successfully performed with SynthaSeal tissue sealant. This may provide a reliable alternative to suture closure.

Anastomosis, Surgical↗

PubMed2001

Duodenal reflux induces cyclooxygenase-2 in the esophageal mucosa of rats: evidence for involvement of bile acids.

BACKGROUND & AIMS: Reflux of duodenal contents including bile acids is believed to contribute to esophageal injury and Barrett's esophagus. Cyclooxygenase (COX)-2, an inducible form of COX, has been implicated in both inflammation and carcinogenesis. In this study, we investigated the effects of bile acids and duodenal reflux on COX-2 expression in cultured esophageal cells and tissue, respectively. METHODS: Immunoblotting and Northern blotting were used to assess the effects of bile acids on COX-2 expression in esophageal cell lines. Immunoblotting and immunohistochemistry were performed to evaluate the effects of duodenal reflux on COX-2 expression and cell proliferation in esophageal tissue. RESULTS: Unconjugated bile acids were about fivefold more potent inducers of COX-2 messenger RNA, COX-2 protein, and prostaglandin synthesis than conjugated bile acids. Acidifying the culture medium sensitized esophageal cells to bile acid-mediated induction of COX-2. The induction of COX-2 by bile acids was mediated by phosphatidylinositol-3 kinase and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. In experimental animals, duodenoesophageal reflux led to esophagitis, marked thickening of the esophageal mucosa, and enhanced expression of COX-2. Increased immunoreactivity for Ki-67 and cyclin D1 indicated that enhanced cell proliferation contributed to mucosal thickening. CONCLUSIONS: Reflux of duodenal contents into the esophagus led to increased COX-2 expression and mucosal thickening. Bile acids are likely to contribute to these effects.

Animals↗

PubMed2001

h-Caldesmon, a novel smooth muscle-specific antibody, distinguishes between cellular leiomyoma and endometrial stromal sarcoma.

The difficulty in distinguishing between smooth muscle and endometrial stromal-derived neoplasms of the uterine corpus is a notorious and clinically relevant problem in pathology of the female genital tract. Immunohistochemistry offers some aid in resolving this difficulty, because the expression of smooth muscle markers is reputed to indicate smooth muscle derivation. This expression, however, is not entirely specific, and difficult cases may still present in which immunohistochemistry is of little help. To explore this problem, the authors evaluated the expression of traditional muscle markers and high-molecular-weight caldesmon (h-cal), an actin and tropomyosin binding protein that has recently been described as a useful muscle marker, in uterine leiomyosarcoma (LMS), cellular leiomyomata (CL), and endometrial stromal sarcoma (ESS). Formalin-fixed and paraffin-embedded tissue sections from nine LMSs, 11 CLs, and 12 ESSs were evaluated with commercially available monoclonal antibodies against smooth muscle actin (SMA), desmin, and h-cal. Established morphologic criteria were used to classify the neoplasms. We found that there was, as expected, a significant difference in the expression of traditional smooth muscle markers (SMA and desmin) between tumors derived from smooth muscle and those derived from endometrial stroma (p = 0.005 for LMS and 0.013 for CL). We further found that h-cal was most useful in distinguishing between CL and ESS (p = 0.01). A significant difference between h-cal expression in LMS versus ESS was not found. Of note, one ESS expressed both SMA and desmin but lacked h-cal expression. Our findings confirm the most useful immunohistochemical data to date; smooth muscle neoplasms are generally distinguishable from endometrial stromal tumors by the expression of conventional muscle markers. We also report here that h-cal is useful more specifically in the differentiation of CL from ESS.

Actins↗

PubMed2001

Mechanism of healing following the Snodgrass repair.

PURPOSE: It has been suggested that healing after tubularized incised plate urethroplasty occurs through re-epithelialization with normal tissue ingrowth or by secondary intent through scarring. We investigated healing in tubularized incised plate urethroplasty. MATERIALS AND METHODS: Hypospadias was created in 5 dogs by incising the ventral urethra, allowed to heal for 21 days and subsequently repaired. During hypospadias creation a tattoo was made longitudinally in the midline dorsal urethral plate. The tattoo was bisected during repair, thus creating 2 distinct lines marking the edges of the incision. A neourethra was tubularized and closed in 2 layers. At 21 days the phallus was harvested, inspected and embedded for histology. RESULTS: The dorsal urethral plate incision contained 2 distinct lines in all samples representing the area of separation between the native and ingrowing urethras. The distance between these lines was 0.9 +/- 0.1 mm. Proximal urethral lumen diameter (3. 3 +/- 0.1 mm.) was not significantly different from that of the neourethral lumen (3.1 +/- 0.1 mm.). Histologically all repairs had intact squamous epithelium. There was normal appearing subepithelial architecture with scant perivascular lymphocytic infiltrates between the tattoos. In contrast, the area around the sutures showed a desmoplastic (fibroblastic) reaction with an inflammatory, primarily neutrophilic response. CONCLUSIONS: Healing of the incision in the dorsal urethral plate during tubularized incised plate urethroplasty occurs by re-epithelialization with normal tissue ingrowth. In contrast, the sutured closure heals with a desmoplastic and inflammatory response.

Animals↗

PubMed2001

Acidic fibroblast growth factor is expressed sequentially in the progression from Barrett's esophagus to esophageal adenocarcinoma.

Acidic fibroblast growth factor 1 (FGF-1) is sequentially accumulated in Barrett's esophagus and its expression in glandular dysplasias is independent of esophageal adenocarcinoma. This suggests that FGF-1 immunohistochemistry could be used as an adjunct to the routine histopathologic diagnosis of dysplasia in Barrett's esophagus. The data also underscore the important role of fibroblast growth factors in tumorigenesis.

Adenocarcinoma↗

PubMed2001

Inducible microsomal prostaglandin E synthase is overexpressed in colorectal adenomas and cancer.

Recently, an inducible microsomal human prostaglandin E synthase (mPGES) was identified. This enzyme converts the cyclooxygenase (COX) product prostaglandin (PG) H(2) to PGE(2), an eicosanoid that has been linked to carcinogenesis. Increased amounts of PGE(2) have been observed in many tumor types including colorectal adenomas and cancers. To further elucidate the mechanism responsible for increased levels of PGE(2) in colorectal tumors, we determined the amounts of mPGES and COX-2 in 18 paired samples (tumor and adjacent normal) of colorectal cancer. With immunoblot analysis, mPGES was overexpressed in 83% of colorectal cancers. COX-2 was also commonly up-regulated in these tumors; marked differences in the extent of up-regulation of mPGES and COX-2 were observed in individual tumors. Immunohistochemistry revealed increased mPGES immunoreactivity in neoplastic cells in both colorectal adenomas and cancers compared with adjacent normal colonic epithelium. Cell culture was used to investigate the regulation of mPGES and COX-2. Chenodeoxycholate markedly induced COX-2 but not mPGES in colorectal cancer cells. Tumor necrosis factor-alpha induced both mPGES and COX-2, but the time course and magnitude of induction differed. As reported previously for COX-2, overexpressing Ras caused a several-fold increase in mPGES promoter activity. Taken together, our results suggest that overexpression of mPGES in addition to COX-2 contributes to increased amounts of PGE(2) in colorectal adenomas and cancer. The mechanisms controlling the expression of these two enzymes are not identical.

Adenocarcinoma↗

PubMed2000

COX-2 is expressed in human pulmonary, colonic, and mammary tumors.

BACKGROUND: The cyclooxygenase (COX) enzyme catalyzes the formation of prostaglandins, which can affect cell proliferation and alter the response of the immune system to malignant cells. The inducible form of COX, COX-2, has been shown to be important in carcinogenesis. METHODS: The authors studied COX-1 and -2 expression in 20 tumors of the lung, colon, and breast (60 total) by using commercially available monoclonal and polyclonal antibodies on formalin fixed, paraffin embedded tissue. Our evaluation also included seven carcinoma-associated colonic adenomas and 10 mammary ductal carcinomas in situ (DCIS). Quantitation of immunoreactivity was accomplished using an immunohistochemical scoring system that approximates the use of image analysis-based systems. RESULTS: Ninety percent of lung tumors (squamous cell carcinomas and adenocarcinomas), 71% of colon adenocarcinomas and 56% of breast tumors (DCIS and infiltrating ductal and lobular carcinomas) expressed COX-2 at a moderate to strong level, which was significantly different from the negligible expression in distant nonneoplastic epithelium (controls; P < 0.0001). Poorly differentiated histologic features were correlated with low COX-2 expression overall, especially in colon carcinomas. Among breast carcinomas, DCIS was more likely to express COX-2 than invasive carcinomas. Adenomatous colonic epithelium showed moderate COX-2 expression, as did adjacent nonneoplastic epithelium. COX-1 immunoreactivity was essentially weak to moderate in all tissues evaluated. CONCLUSIONS: COX-2 expression is upregulated in well and moderately differentiated carcinomas of the lung, colon, and breast whereas COX-1 appears to be constitutively expressed at low levels. A possible COX-2 paracrine effect is suggested by moderate immunoreactivity in adjacent nonneoplastic epithelium.

Breast↗

PubMed2000

Desmoplastic small round cell tumor with primary ovarian involvement: case report and review.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive, malignant neoplasm that has recently been characterized. It has not been associated with a primary visceral organ. In women, cases are even more rare and often have some ovarian involvement. CASE: An 11-year-old girl presented with abdominal pain, nausea, and vomiting. A CT scan revealed a large heterogeneous pelvic mass with cystic components and an 8-cm midabdominal mass. During exploratory laparotomy, the patient was found to have a pelvic mass measuring 12. 9 cm replacing normal ovarian tissue. The midabdominal mass was also removed. Pathology, cytology, and immunohistochemistry confirmed a desmoplastic small round cell tumor. Even with aggressive surgical and medical intervention, the patient died 11 months after initial diagnosis. CONCLUSION: We present a rare small cell tumor that is associated with ovarian involvement. The prognosis in these patients is extremely poor and very few survivals have been reported.

Child↗

PubMed2000

Tumor suppressor gene, cell surface adhesion molecule, and multidrug resistance in Müllerian serous carcinomas: clinical divergence without immunophenotypic differences.

OBJECTIVES: We hypothesize that differences in the expression of selected tumor suppressor genes, cell surface adhesion molecules, and multidrug resistance glycoproteins could account for some of the reported differences between uterine serous carcinoma (USC) and extrauterine serous carcinomas (ESC), including ovarian and primary peritoneal carcinoma (OSC and PSC, respectively). METHODS: We studied the expression of the following antigens in 20 USCs, 20 OSCs, and 10 PSCs: p53 and mdm-2 (tumor suppressor genes), CD44 and CD44v6 (cell surface adhesion molecules), and the p-glycoprotein (a multidrug resistance protein recognized by two antibodies, C494 and JSB1). We further studied chemotherapeutic drug resistance by examining reports prepared using the Oncotech Extreme Drug Resistance Assay from 24 of the 50 study patients. Clinical data were obtained from medical record review. RESULTS: USC, OSC, and PSC patients were similar with respect to mean age at diagnosis, mean gravidity, mean parity, personal history of breast cancer, percentage treated with chemotherapy, and survival at 3 and 5 years postdiagnosis. Significant clinical differences included a high prevalence of nulliparity in OSC (P = 0.05), a low prevalence of Caucasian race in USC (P = 0.008), a paucity of stage I patients in OSC and PSC (P = 0.03), a high prevalence of familial breast cancer in OSC (P = 0.06), and superior 2-year survival in OSC (P = 0.02). Seventy-five percent of USCs, 52% of OSCs, and 60% of PSCs expressed p53. Five percent of USCs, 19% of OSCs, and 0% of PSCs expressed mdm-2. Forty percent of USCs, 33% of OSCs, and 10% of PSCs expressed CD44. None of the USCs, OSCs, or PSCs expressed CD44v6. Sixty-one percent of USCs and OSCs and 82% of PSCs expressed C494 while 17% of USCs, 19% of OSCs, and 20% of PSCs expressed JSB1. None of these apparent differences was statistically significant. USC, OSC, and PSCs patients did not demonstrate significant differences with respect to extreme drug resistance. However, the following trends were noted (P = 0.06): more prevalent low drug resistance for cyclophosphamide in OSC compared with USC and more prevalent extreme drug resistance for etoposide in OSC compared with USC. CONCLUSIONS: Therefore, despite significant clincial differences, the USCs and ESCs in our series do not differ significantly with respect to the expression of the tumor suppressor genes, cell surface adhesion molecules, and drug resistance proteins studied. It is premature, however, to recommend that USCs and ESCs should be treated identically.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2000

Laser-assisted demucosalized gastrocystoplasty with autoaugmentation in a canine model.

OBJECTIVES: Laser-assisted autoaugmentation gastrocystoplasty has been performed successfully. Experiments were performed to determine the optimal laser for tissue welding during demucosalized autoaugmentation gastrocystoplasty using both a 1.9-microm diode and a 1.32-microm neodymium:yttrium-aluminum-garnet (Nd:YAG) laser with and without thermal control. METHODS: Autoaugmentation gastrocystoplasty was performed on 18 female mongrel dogs. Anastomoses were performed by either suture or laser welding with a 50% human albumin solution. A 1.9-microm diode laser was compared with a 1.32-microm Nd:YAG laser with and without thermal control. In vivo canine bladder capacity measurements were performed both before gastrocystoplasty and at euthanasia. The animals were studied on days 4 and 14. Samples of the anastomotic area from each group were taken to measure tensile strength. Histologic samples were assessed for tissue damage. RESULTS: There was a significant increase in bladder volume in the 4-day group compared with pregastrocystoplasty values. Both the 1.9-microm diode laser and suture control dogs with the 14-day repairs had significantly more tensile strength than their 4-day counterparts. In contrast, no statistical difference was found between the 4 and 14-day 1.32-microm Nd:YAG groups. The suture control group had evidence of minor tissue devitalization at the anastomosis at both 4 and 14 days. The 1.9 and 1.32-microm laser groups both had evidence of tissue devitalization at 4 and 14 days. The 1.32-microm laser group had primarily severe tissue injury. The laser groups at 14 days demonstrated an inflammatory reaction that was localized to the albumin. CONCLUSIONS: Demucosalized gastrocystoplasty with autoaugmentation can be safely and successfully performed with a 1.9-microm diode laser without significant differences in tensile strength when compared with suture controls. The 1.32-microm Nd:YAG laser can also be successfully used; however, the long-term results appear to be inferior to the 1.9-microm diode laser.

Anastomosis, Surgical↗

PubMed2000

A comparison of cell cycle markers in well-differentiated lobular and ductal carcinomas.

Infiltrating lobular carcinoma (ILC) and infiltrating ductal carcinoma (IDC) are similar in many respects and their histologic features occasionally overlap. Despite the many similarities, some clinical follow-up data and the patterns of metastasis suggest that ILC and IDC are biologically distinct. Unfortunately, most breast cancer research has focused almost exclusively on the ductal subtype or has not stressed the biologic or molecular genetic distinctions between breast carcinoma subtypes. Several reports have suggested the possibility that ILCs and IDCs differ with respect to expression of antigens involved in proliferation and cell cycle regulation. Therefore, we undertook an immunohistochemical evaluation of cell cycle related antigens in ILCs, including histologic variants thought to represent aggressive neoplasms, and IDCs matched for histologic grade (Modified Bloom-Richardson Grade I). We believe that different antigen expression profiles could elucidate the biological distinctiveness of breast carcinoma subtypes and possibly provide diagnostically relevant information. We studied the expression of the following antigens in 28 archived, formalin-fixed ILCs and 34 well-differentiated IDCs: estrogen receptor (ER), progesterone receptor (PR), Her 2-neu, mib-1, cyclin D1, p27, p53, mdm-2 and bcl-2. 94% of ILCs and 100% of IDCs expressed ER; 75% of ILCs and 76% of IDCs expressed PR; 4% of ILCs and 13% of IDCs expressed c cerb B-2; ILCs and IDCs both expressed mib-1 in approximately 10% of lesional cells; 82% of ILCs and 54% of IDCs expressed cyclin D1; 90% of ILCs and 83% IDCs expressed p27 strongly; 4% of ILCs and 4% of IDCs expressed p53, 25% of ILCs and 33% of IDCs expressed mdm-2; 96% of ILCs and 100% of IDCs expressed bcl-2. None of the apparent differences were statistically significant. The ILC variants demonstrated immunophenotypes that were essentially similar to ILCs of the usual type. We conclude that ILCs and well-differentiated IDCs show similar proliferation and cell cycle control antigen profiles. Despite their unusual histologic features, most ILC variants appear to maintain a characteristic ILC immunophenotype.

Antigens, Neoplasm↗

PubMed2000

Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction.

BACKGROUND: Unilateral ureteral obstruction (UUO) is characterized by progressive renal atrophy, renal interstitial fibrosis, an increase in renal transforming growth factor-beta (TGF-beta), and renal tubular apoptosis. The present study was undertaken to determine the effect of a monoclonal antibody to TGF-beta (1D11) in UUO. METHODS: Mechanical stretch was applied to tubular epithelial cells (NRK-52E) by a computer-assisted system. Three doses of 1D11 (either 0.5, 2, or 4 mg/rat) were administered to rats one day prior to UUO and every two days thereafter, and kidneys were harvested at day 13. Fibrosis was assessed by measuring tissue hydroxyproline and mRNA for collagen and fibronectin. Apoptosis was assessed with the terminal deoxy transferase uridine triphosphate nick end-labeling assay. TGF-beta levels were determined by bioassay. Western blot and immunostaining were used to identify proliferating cell nuclear antigen (PCNA), p53, bcl-2, and inducible nitric oxide synthase (iNOS). RESULTS: Stretch significantly induced apoptosis in NRK-52E cells, which was accompanied by an increased release of TGF-beta; 1D11 (10 microg/mL) totally inhibited stretch-induced apoptosis. Control obstructed kidney contained 20-fold higher TGF-beta as compared with its unobstructed kidney; 1D11 neutralized tissue TGF-beta of the obstructed kidney. Control obstructed kidney exhibited significantly more fibrosis and tubular apoptosis than its unobstructed counterpart, which was blunted by 1D11. In contrast, 1D11 significantly increased tubular proliferation. p53 immunostaining was localized to renal tubular nuclei of control obstructed kidney and was diminished by 1D11. In contrast, bcl-2 was up-regulated in the 1D11-treated obstructed kidney. Total NOS activity and iNOS activity of the obstructed kidney were increased by 1D11 treatment. CONCLUSION: The present study strongly suggests that an antibody to TGF-beta is a promising agent to prevent renal tubular fibrosis and apoptosis in UUO.

Animals↗

PubMed2000

Endometrial intraepithelial carcinoma with associated peritoneal carcinomatosis.

Endometrial intraepithelial carcinoma (EIC) is a recently described entity, defined as a noninvasive, cytologically malignant lesion that replaces the endometrial surface epithelium. EIC frequently coexists with uterine serous carcinoma (USC) and is hypothesized to be its precursor lesion. However, the clinical significance and biologic potential of finding EIC without USC is not known. We report three postmenopausal women with EIC alone who were found to have multiple, synchronous foci of extrauterine serous carcinoma at presentation. Because the clinical findings in these patients simulated primary peritoneal serous carcinoma (PSC), we compared the clinicopathologic features of these cases with a group of nine bona fide PSCs for which exhaustively sectioned endometria, fallopian tubes, and ovaries were available for review. The average age of the EIC patients was 73 years. Two patients presented with abdominal distention and one with vaginal bleeding. Hysterectomy in each case showed endometrial polyps with EIC, but without invasive USC, in a background of atrophic endometrium. Bilateral salpingo-oophorectomy and staging showed serous carcinoma involving the ovarian hilum, the surfaces of the fallopian tubes and ovaries, in addition to peritoneal carcinomatosis. p53 overexpression was observed in both EIC and the extrauterine deposits of serous carcinoma in each case. The average age of the PSC patients was 66 years. All nine patients presented with abdominal distention. EIC was not identified in any of the hysterectomy specimens. Bilateral salpingo-oophorectomies, omentectomies, and peritoneal biopsies showed peritoneal carcinomatosis, including bulky peritoneal tumor deposits, but only minimal ovarian surface involvement. p53 overexpression was observed in seven cases. These findings indicate that EIC without coincident USC can be associated with invasive, extrauterine serous carcinomatosis. We did not, however, find any significant differences between the clinicopathologic features of primary extrauterine serous carcinomas (PSCs) and those associated with EIC. We conclude that the finding of EIC in an endometrial curettage specimen should prompt a thorough search for an invasive uterine and/or extrauterine serous carcinoma. Conversely, an endometrial origin should be excluded in patients with peritoneal carcinomatosis.

Aged↗

PubMed2000

Cyclin D1 expression in high-grade endometrial carcinomas--association with histologic subtype.

Endometrial endometrioid adenocarcinoma (EC) and serous carcinoma (ESC) are associated with different epidemiologic risk factors, precursor lesions, morphology, and survival outcomes. They also possess distinct molecular profiles. We investigated the expression of cyclin D1, a member of the G1 cyclin family that regulates the G1/S transition in the cell cycle, and estrogen and progesterone receptors (ERs and PRs, respectively) in a group of ECs and ESCs matched for histological grade. We also sought to correlate the expression of cyclin D1 with ER and PR because cyclin D1 has been reported to stimulate transcription of ER- and PR-regulated genes (1,2). We hypothesize that cyclin D1 expression covaries with histologic subtype and is related to the expression of ER and PR. Twenty ESCs and 21 ECs were examined histologically and evaluated immunohistochemically for cyclin D1, ER, and PR using commercially available monoclonal antibodies in archival, formalin-fixed, and paraffin-embedded tissue. Three ESCs (15%) and 10 ECs (48%) expressed cyclin D1 (p = 0.02). Twelve ESCs (60%) and 16 ECs (76%) expressed ER, which is not significantly different. ER-positive ECs were significantly more likely to express cyclin D1 compared with ER-positive ESCs (p = 0.03), but a relationship between cyclin D1 and ER expression in EC was not found. We also did not find a significant relationship between cyclin D1 and PR expression. Therefore, cyclin D1 expression in poorly differentiated endometrial carcinomas is associated with endometrioid histology. This is consistent with pathobiologic divergence in poorly differentiated endometrial carcinomas.

Adenocarcinoma↗